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WO2019241751A1 - Inhibiteurs de ssao et leurs utilisations - Google Patents

Inhibiteurs de ssao et leurs utilisations Download PDF

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Publication number
WO2019241751A1
WO2019241751A1 PCT/US2019/037380 US2019037380W WO2019241751A1 WO 2019241751 A1 WO2019241751 A1 WO 2019241751A1 US 2019037380 W US2019037380 W US 2019037380W WO 2019241751 A1 WO2019241751 A1 WO 2019241751A1
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Prior art keywords
alkyl
compound
solvate
pharmaceutically acceptable
acceptable salt
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Ceased
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PCT/US2019/037380
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English (en)
Inventor
Nicholas D. Smith
Andrew R. Hudson
Mi Chen
Johnny Y. Nagasawa
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Metacrine Inc
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Metacrine Inc
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Publication of WO2019241751A1 publication Critical patent/WO2019241751A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/46—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/22—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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    • C07C271/44—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
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    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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Definitions

  • SSAO semicarbazide-sensitive amine oxidase
  • SSAO Semicarbazide-sensitive amine oxidase
  • AOC3 amine oxidase, copper containing 3
  • VAP-l vascular adhesion protein 1
  • SSAO is an enzyme that exists both as a membrane-bound and a soluble isoform. It is highly expressed in the lung, aorta, liver and ileum. SSAO has been implicated in the pathogenesis of liver diseases (Weston, C.J. et ah, J Neural. Transm. 2011, 118, 1055-1064).
  • SSAO inhibition is a treatment modality for liver diseases or conditions such as fatty liver disease.
  • SSAO inhibitors and uses thereof.
  • described herein is a compound that has the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:
  • R 1 is C 2-6 alkenyl, C 2-6 alkynyl, a saturated monocyclic C 2-7 heterocycloalkyl, saturated bridged bicyclic C 2- 9heterocycloalkyl, or saturated spirocyclic C 2- 9heterocycloalkyl, wherein C 2- 6 alkenyl, C 2-6 alkynyl, saturated monocyclic C 2-7 heterocycloalkyl, saturated bridged bicyclic C 2- 9heterocycloalkyl, or saturated spirocyclic C 2-9 heterocycloalkyl are optionally
  • each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, -R 14a , - OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , - N(R U )S(0) 2 R 12 , -C(0)
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, R 14a , -OR 8 , - SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3- 6cycloalkyl, C 2- 9heterocycloalkyl, C 6-l0 aryl, Ci.gheteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -
  • R 5 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R 4 and R 5 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14d ;
  • R 6 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl
  • R 7 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- l0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e ;
  • each R 8 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14c , R 14d , R 14e , R 14f , R 14g , R 14h , R 14i , R 14j , R 14k , R 141 , R 14m , and R 14n are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, -CH 2 -C 3-6C ycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 .
  • 6cycloalkyl, -CH 2 -C3-6cycloalkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 . ioaryl, -CH 2 -C 6 -ioaryl, and Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci.
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-i oaryl, and Ci.gheteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-i oaryl, and Ci.gheteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2- 9heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-i oaryl, and Ci_ 9 heteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • R 21 is selected from H and Ci -6 alkyl
  • R 22 is selected from Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2- 9heterocycloalkyl, C 6-i oaryl, and Ci.gheteroaryl, wherein C 2-6 alkenyl, C 2-6 alkynyl, C 2- 9heterocycloalkyl, C 6-i oaryl, and Ci. gheteroaryl are optionally substituted with one, two, or three R 14j ;
  • R is selected from H and Ci -6 alkyl; or R and R together with the nitrogen to which they are attached, form a C 2- 9heterocycloalkyl ring optionally substituted with one, two, or three R 14k ;
  • R 24 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- gheterocycloalkyl, C 6-i oaryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-i oaryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 141 ;
  • R is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R and R together with the nitrogen to which they are attached, form a C 2- 9heterocycloalkyl ring optionally substituted with one, two, or three R 14m ;
  • R 26 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14n ;
  • n 0, 1, 2, 3, or 4;
  • p 0 or 1.
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein Y is -R 1 .
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein Y is -I ⁇ -R 1 .
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein Y is -L 2 -R ⁇
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein Y is -I ⁇ -L ⁇ R 1 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9
  • R 1 is a saturated monocyclic C 2- 7 heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl selected from pyrrolidinyl, piperidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, azetidinyl, and tetrahydropyranyl, wherein pyrrolidinyl, piperidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, azetidinyl, and tetrahydropyranyl are optionally substituted with one, two, or three R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci.
  • R 1 is piperidinyl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, oxo, - CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -R 14a , - OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )
  • R 1 is a saturated bridged bicyclic C 2-9 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, oxo, -
  • L 3 is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 N(H)CH 2 -, or -CH 2 N(CH 3 )CH 2 -, and q is 0, 1, or 2.
  • L 3 is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 N(H)CH 2 -, or -CH 2 N(CH 3 )CH 2 -, and q is 0, 1, or 2.
  • q is 0, 1, or 2.
  • L 3 is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 N(H)CH 2 -, or -CH 2 N(CH 3 )CH 2 -, and q is 0, 1, or 2.
  • L 3 is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 N(H)CH 2 -, or -CH 2 N(CH 3 )CH 2 -, and q is 0, 1, or 2.
  • L 3 is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 N(H)CH 2 -, or -CH 2 N(CH 3 )CH 2 -, and q is 0, 1, or 2.
  • L 3 is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 N(H)CH 2 -, or -CH 2 N(CH 3 )CH 2 -, and q is 0, 1, or 2.
  • w 1 , w 2 , w 3 , and w 4 are each independently selected from 1 and 2.
  • w 1 , w 2 , w 3 , and w 4 are each independently selected from 1 and 2.
  • R 1 is a saturated monocyclic C 2- 7heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C2-9heterocycloalkyl, C 6 - l oaryl, Ci.gheteroaryl, -R 14a , -OR 8 , -SR 8 , - N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 - l oaryl, Ci.gheteroaryl, -R 14a , -OR 8 , -SR 8 , - N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -
  • each R la is independently selected from oxo, Ci -6 alkyl, Ci.gheteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • each R la is independently selected from oxo, Ci -6 alkyl, and -C(0)R 12 .
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.
  • R 14a gheteroaryl, R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), - OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , - C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , -S(0) 2 N(R 9 )(R 10 ), and -OC(0)R 12 .
  • Rib is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- gheterocycloalkyl, C 6-i oaryl, Ci.gheteroaryl, R 14a , -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), - C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ).
  • R lb is independently selected from H, Ci -6 alkyl, C3 -6 cycloalkyl, and R 14a .
  • each R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C2-9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6.l0 aryl, Ci.
  • gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, -OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)OR 16 , -C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), -0C(0)N(R 16 )(R 17 ), - N(R 18 )C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)0R 19 , -N(R 18 )C(0)R 19 , -N(R 18 )S(0) 2 R 19 , -C(0)R 19 , - S(0) 2 R 19 , -S(0) 2 N(R 16 )(R 17 ), and -OC(0)
  • each R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, - CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 - C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci.
  • each R 9 is independently selected from H and Ci -6 alkyl optionally substituted with one, two, or three R 14g .
  • each R 9 is independently selected from H and unsubstituted Ci -6 alkyl.
  • each R 12 is independently selected from Ci -6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci. 9 heteroaryl, wherein Ci -6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • each R 12 is independently selected from Ci -6 alkyl and Ci -9 heteroaryl, wherein Ci -6 alkyl and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • each R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 .
  • each R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 and each R 141 is independently selected from - OH, -NH 2 , and -N(H)CH 3 .
  • Y is -R 2 .
  • R 2 is -C(0)0R 4 , -0C(0)N(R 4 )(R 5 ), - N(R 6 )C(0)N(R 4 )(R 5 ), -N(R 6 )C(0)0R 7 , -N(R 6 )S(0) 2 R 7 , or -CH 2 C(0)N(R 24 )(R 25 ).
  • R 4 is selected from H, Ci -6 alkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C3 -6 cycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, and Ci.
  • gheteroaryl are optionally substituted with one, two, or three R 14c .
  • R 4 is selected from H, Ci -6 alkyl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c .
  • R 5 is H.
  • R 7 is selected from Ci -6 alkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 6 -i 0 aryl, and Ci.
  • gheteroaryl are optionally substituted with one, two, or three R 14e .
  • R 7 is selected from Ci -6 alkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 6 -i 0 aryl, and Ci.
  • 9heteroaryl are optionally substituted with one, two, or three R 14e .
  • R 24 is selected from H, Ci -6 alkyl, C3 -6 cycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C3 -6 cycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, and Ci.
  • 9heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 25 is H.
  • each R 3 is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 is
  • ioaryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14b .
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2- 9heterocycloalkyl, Ci -9 heteroaryl, -OR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , - C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , -S(0) 2 N(R 9 )(R 10 ), wherein C ⁇ alkyl, C 2-9 heterocycloalkyl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14b .
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, -OR 8 , -N(R 9 )(R 10 ), wherein Ci -6 alkyl is optionally substituted with one, two, or three R 14b .
  • n is 1.
  • n is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
  • n is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
  • X is -CH 2 -.
  • R 20 is H.
  • Z is F.
  • Z is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is Cl.
  • Z is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is H.
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.
  • the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, or oral administration.
  • the pharmaceutical composition is formulated for administration to a mammal by oral administration.
  • the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.
  • described herein is a method of treating a disease or condition in a mammal that would benefit from SSAO inhibition comprising administering a compound as described herein, or pharmaceutically acceptable salt, or solvate thereof, to the mammal in need thereof.
  • the disease or condition is a liver condition.
  • the compound is administered to the mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.
  • described herein is a method of treating or preventing any one of the diseases or conditions described herein comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, to a mammal in need thereof.
  • a method for the treatment or prevention of a liver condition in a mammal comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, to the mammal in need thereof.
  • the liver condition is amenable to treatment with an SSAO inhibitor.
  • the method further comprises administering a second therapeutic agent to the mammal in addition to the compound described herein, or a pharmaceutically acceptable salt, or solvate thereof.
  • a method of treating or preventing a liver disease or condition in a mammal comprising administering to the mammal a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof.
  • the liver disease or condition is nonalcoholic steatohepatitis (NASH), or nonalcoholic fatty liver disease (NAFLD).
  • the non-alcoholic liver disease or condition is nonalcoholic steatohepatitis (NASH).
  • the non alcoholic liver disease or condition is nonalcoholic steatohepatitis (NASH) and is accompanied by liver fibrosis. In some embodiments, the non-alcoholic liver disease or condition is nonalcoholic steatohepatitis (NASH) without liver fibrosis.
  • NASH nonalcoholic steatohepatitis
  • the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation; and/or (e) administered by nasal administration; or and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) administered non-systemically or locally to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which the compound is administered once a day to the mammal or the compound is administered to the mammal multiple times over the span of one day.
  • the compound is administered on a continuous dosing schedule.
  • the compound is
  • any of the aforementioned aspects involving the treatment of a disease or condition are further embodiments comprising administering at least one additional agent in addition to the administration of a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III) described herein, or a pharmaceutically acceptable salt thereof.
  • each agent is administered in any order, including simultaneously.
  • the mammal or subject is a human.
  • compounds provided herein are administered to a human.
  • compounds provided herein are orally administered.
  • R 1 is C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, or Ci -9 heteroaryl, wherein C 2-6 alkenyl, C 2- 6 alkynyl, C 2-9 heterocycloalkyl, or Ci -9 heteroaryl are optionally substituted with one, two, three, four, or five R la ;
  • each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -0
  • R 4 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c ;
  • R 5 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R 4 and R 5 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14d ;
  • R 6 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl
  • R 7 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 - !oaryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14e ;
  • each R 8 is independently selected from H, Ci -6 alkyl, C2 -6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C2 -6 alkenyl, C 2 - 6alkynyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6.l0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3.6 cycloalkyl, C 2 -9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2 - 6alkynyl, C 3.6 cycloalkyl, C 2 -9heterocycloalkyl, C 6.l0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3.6 cycloalkyl, C 2 - gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3.6 cycloalkyl, C 2 -9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14c , R 14d , R 14e , R 14f , R 14g , R 14h , R 14i , R 14j , R 14k , R 141 , R 14m , and R 14n are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-g heterocycloalkyl, -CH2-C 2- 9heterocycloalkyl, C 6 .
  • loaryl, -CH 2 -C 6 -ioaryl, and Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci.
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycl
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • R 21 is selected from H and Ci -6 alkyl
  • R 22 is selected from Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci. 9heteroaryl are optionally substituted with one, two, or three R 14j ;
  • R 23 is selected from H and Ci -6 alkyl; or R 22 and R 23 together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14k ;
  • R 24 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • R is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R and R together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14m ;
  • R 26 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14n ;
  • n 0, 1, 2, 3, or 4;
  • p 0 or 1.
  • R 1 is C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, or Ci -9 heteroaryl, wherein C 2-6 alkenyl, C 2- 6 alkynyl, C 2-9 heterocycloalkyl, or Ci -9 heteroaryl are optionally substituted with one, two, three, four, or five R la ;
  • each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -0C(0)R
  • R 4 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c ;
  • R 5 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R 4 and R 5 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14d ;
  • R 6 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl
  • R 7 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 - ioaryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - 9heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e ;
  • each R 8 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2 - 6alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14c , R 14d , R 14e , R 14f , R 14g , R 14h , R 14i , R 14j , R 14k , R 141 , R 14m , and R 14n are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, - OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)0R 16 , -C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), - 0C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)
  • 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2 - gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci.
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- gheterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • R 21 is selected from H and Ci -6 alkyl
  • R 22 is selected from Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci.gheteroaryl, wherein C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci. gheteroaryl are optionally substituted with one, two, or three R 14j ;
  • R is selected from H and Ci -6 alkyl; or R and R together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14k ;
  • R 24 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6C ycloalkyl, C 2- gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 141 ;
  • R is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R and R together with the nitrogen to which they are attached, form a C 2- 9heterocycloalkyl ring optionally substituted with one, two, or three R 14m ;
  • R 26 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6C ycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6C ycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14n ; n is 0, 1, 2, 3, or 4; and
  • p 0 or 1.
  • SSAO Semicarbazide-sensitive amine oxidase
  • AOC3 amine oxidase, copper containing 3
  • VAP-l vascular adhesion protein 1
  • AOC3 amine oxidase, copper containing 3
  • VAP-l vascular adhesion protein 1
  • AOC3 has two closely related genes in the human genome.
  • AOC1 which corresponds to a diamine oxidase (DAO) found in gut, lung and kidney (Chassande, O. et al., J. Biol. Chem., 1994, 269: 14484-14489) and AOC2, a SSAO with expression in the eye (Imamura, Y. et al., Genomics, 1997, 40: 277-283).
  • AOC4 is a sequence that does not lead to a functional gene product in humans (Schwelberger, H. G. J. Neural Transm.,
  • SSAO has at least two physiological functions.
  • SSAO functions as an amine oxidase in which primary amines may be oxidized to aldehydes, leading to the release of ammonia and hydrogen peroxide upon regeneration of the cofactor 2,4,5-trihydroxy-phenyl-alanyl- quinone (TPQ).
  • Endogenous substrates include methylamine, dopamine and aminoacetone.
  • Aldehyde products generated under high AOC3 levels can be highly reactive, leading to glycation end products which may be regarded as drivers of diabetes associated inflammatory mechanisms (Mathys, K. C. et al., Biochem. Biophys. Res. Commun., 2002, 297: 863-869).
  • hydrogen peroxide produced by SSAO can directly lead to direct cellular damage or be sensed by the tissue as a messenger of inflammation and so lead to further propagation of inflammatory processes.
  • SSAO has cell adhesion activity, with SSAO having been shown to be important for leukocyte rolling, adhesion and transmigration in response to inflammatory stimuli (Salmi et al, Antoxidants and Redox Signaling, 2017). Both activities are associated with inflammatory processes.
  • SSAO was also shown to play a role in extravasation of inflammatory cells from the circulation to sites of inflammation (Salmi M.; Trends Immunol. 2001, 22, 21 1-216).
  • SSAO antibodies have been shown to attenuate inflammatory processes by blocking the adhesion site of the SSAO protein.
  • inhibitors of the amine oxidase activity of SSAO have been found to interfere with leukocyte rolling, adhesion and extravasation and, in a similar manner to SSAO antibodies, exhibit anti-inflammatory properties.
  • SSAO has been implicated in the pathogenesis of liver diseases such as fatty liver disease (Weston, C.J. et al., J Neural. Transm. 2011, 118, 1055-1064).
  • serum SSAO is elevated in patients with fatty liver disease and correlates with histological markers of liver injury.
  • SSAO has been shown to contribute to liver fibrosis in preclinical models induced by chemical injury and diet induction.
  • SSAO knock-out animals, or SSAO inhibition using an antibody are protective in both of these models (Weston et al; J. Clin. Invest., 2015, 125, 2, 501-520).
  • Non-alcoholic fatty liver disease is associated with excessive fat in the liver (steatosis) and in some cases progresses to NASH, which is defined by the histologic hallmarks of inflammation, cell death, and fibrosis.
  • primary NASH is associated with insulin resistance
  • secondary NASH is caused by medical or surgical conditions, or drugs such as, but not limited to, tamoxifen.
  • NASH progresses to advanced fibrosis, hepatocellular carcinoma, or end-stage liver disease requiring liver transplantation.
  • NASH develops as a result of triglyceride (TGs) imbalance.
  • TGs triglyceride
  • dysfunctional adipocytes secrete pro-inflammatory molecules such as cytokines and chemokines leading to insulin resistance and a failure of lipolysis suppression in the adipocytes.
  • this failure of lipolysis suppression leads to a release of free fatty acids (FFAs) into the circulation and uptake within the liver.
  • FFAs free fatty acids
  • over accumulation of FFAs in the form of triglycerides (TGs) in lipid droplets leads to oxidative stress, mitochondrial dysfunction, and upregulation of pro-inflammatory molecules.
  • an SSAO inhibitor disclosed herein is used in the treatment of non alcoholic steatohepatitis (NASH).
  • the SSAO inhibitor reduces NASH the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more.
  • NASH is reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%.
  • the level of NASH is relative to the level of NASH in a subject not treated with the SSAO inhibitor.
  • an SSAO inhibitor disclosed herein is used in the treatment of NAFLD.
  • the SSAO inhibitor reduces NAFLD in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more.
  • NAFLD is reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%.
  • the level of NAFLD is relative to the level of NAFLD in a subject not treated with the SSAO inhibitor.
  • Hepatocyte ballooning a feature denoting cellular injury, is a feature of NASH.
  • Ballooning is a feature that denotes progressive NAFL (types 3 and 4). The term applies to enlarged, swollen-appearing hepatocytes; the affected cells are often intermixed in areas of steatosis and, in classic steatohepatitis, in the perivenular regions. Hepatocellular ballooning is most commonly noted in regions of H & E-detectable perisinusoidal fibrosis. Ballooned hepatocytes are most easily noted when they contain MH (either typical or poorly formed). Hepatocyte ballooning is a structural manifestation of microtubular disruption and severe cell injury.
  • an SSAO inhibitor disclosed herein reduces liver ballooning in a subject.
  • the SSAO inhibitor reduces liver ballooning in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more.
  • liver ballooning is reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%.
  • the liver ballooning is relative to the level of liver ballooning in a subject not treated with the SSAO inhibitor.
  • Compounds described herein, including pharmaceutically acceptable salts, prodrugs, active metabolites and pharmaceutically acceptable solvates thereof, are SSAO inhibitors.
  • SSAO inhibitors and uses thereof. In some aspects, described herein are SSAO inhibitors and uses thereof. In some aspects, described herein are SSAO inhibitors and uses thereof. In some aspects, described herein are SSAO inhibitors and uses thereof.
  • Z is H, F, or Cl
  • R 1 is C 2-6 alkenyl, C 2-6 alkynyl, a saturated monocyclic C 2.7 heterocycloalkyl, saturated bridged bicyclic C 2-9 heterocycloalkyl, or saturated spirocyclic C 2-9 heterocycloalkyl, wherein C 2- 6 alkenyl, C 2-6 alkynyl, saturated monocyclic C 2- 7heterocycloalkyl, saturated bridged bicyclic C 2-9 heterocycloalkyl, or saturated spirocyclic C 2-9 heterocycloalkyl are optionally
  • each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-l0 aryl, Ci -9 heteroaryl, -R 14a , - OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , - N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0)
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cydoalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, R 14a , -OR 8 , - SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , - S
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -0
  • R 4 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6C ydoalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c ;
  • R 5 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R 4 and R 5 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14d ;
  • R 6 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl
  • R 7 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 - ioaryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - 9heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e ;
  • each R 8 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2 - 6alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2 - 6alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14c , R 14d , R 14e , R 14f , R 14g , R 14h , R 14i , R 14j , R 14k , R 141 , R 14m , and R 14n are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 .
  • l 0 aryl, -CH 2 -C 6-i oaryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci.
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • R 21 is selected from H and Ci -6 alkyl
  • R 22 is selected from Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci. 9heteroaryl are optionally substituted with one, two, or three R 14j ;
  • R 23 is selected from H and Ci -6 alkyl; or R 22 and R 23 together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14k ;
  • R 24 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • R is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R and R together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14m ;
  • R 26 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14n ;
  • n 0, 1, 2, 3, or 4;
  • p 0 or 1.
  • substituents are selected from among a subset of the listed alternatives.
  • X is -0-, -S-, -S(0) 2 -, -N(R 13 )-, or -C(R 13 ) 2 -.
  • X is -0-.
  • X is -S-.
  • X is - S(0) 2 -.
  • X is -N(R 13 )-.
  • X is -N(H)-.
  • X is -C(R 13 ) 2 -.
  • X is -CH 2 -.
  • Z is H, F, or Cl. In some embodiments, Z is F. In some embodiments,
  • Z is Cl. In some embodiments, Z is H.
  • p is 1. In some embodiments, p is 0.
  • Y is -R 1 . In some embodiments, Y is -I ⁇ -R 1 . In some embodiments,
  • Y is -L 2 -R ⁇ In some embodiments, Y is I ⁇ -L ⁇ R 1 . In some embodiments, Y is -L 2 - I ⁇ -R 1 . In some embodiments, L 1 is -0-. In some embodiments, L 1 is -CH 2 -. In some embodiments, L 2 is -CH 2 -.
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, three, or four R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-i oaryl, Ci.gheteroaryl, - R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-i0 aryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)OR 12 , -N(R u )C(0)OR 12 , -N(R u )
  • R 1 is a saturated monocyclic C 2- 7 heterocycloalkyl optionally substituted with one or two R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0)
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one or two R la and each R la is independently selected from oxo, Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one or two R la and each R la is independently selected from oxo, Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated monocycl
  • monocyclic C2-7heterocycloalkyl optionally substituted with one R la and R la is selected from Ci. ealkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and - S(0) 2 R 12 .
  • R 1 is an unsubstituted saturated monocyclic C 2- 7heterocycloalkyl.
  • R 1 is a saturated monocyclic C 2- 7heterocycloalkyl substituted with one R la and R la is selected from C ⁇ alkyl, Ci -9 heteroaryl, -R 14a , -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated monocyclic C 2- 7heterocycloalkyl substituted with one R la and R la is selected from C ⁇ alkyl, Ci -9 heteroaryl, -R 14a , -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated
  • R 1 is a saturated monocyclic C 2- 7heterocycloalkyl substituted with one R la and R la is -S(0) 2 R 12 .
  • R 12 is independently selected from Ci -6 alkyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl and Ci -9 heteroaryl, wherein Ci -6 alkyl and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 and each R 141 is independently selected from -OH, -NH 2 , and -N(H)CH 3 .
  • R 1 is a saturated monocyclic C 2- 7heterocycloalkyl substituted with one R la and R la is -C(0)OR 9 . In some embodiments, R 1 is a saturated monocyclic C 2- 7heterocycloalkyl substituted with one R la and R la is -C(0)N(R 9 )(R 10 ). In some embodiments,
  • R 1 is a saturated monocyclic C 2- 7heterocycloalkyl substituted with one R la and R la is - C(0)C(0)N(R 9 )(R 10 ).
  • R 9 is independently selected from H and Ci -6 alkyl optionally substituted with one, two, or three R 14g .
  • R 9 is independently selected from H and unsubstituted Ci -6 alkyl.
  • R 10 is H. In some embodiment
  • R 1 is a saturated monocyclic C 2- 7heterocycloalkyl substituted with one R la and R la is -R 14a .
  • R 14a is independently selected from Ci -6 alkyl, C 2-9 heterocycloalkyl, - CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-9 heterocycloalkyl, -CH 2 - C 2-9 heterocycloalkyl, C 6.l0 aryl, Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci.
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH2-C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6.l0 aryl, Ci.
  • gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, -OR 15 , -N(R 16 )(R 17 ), - C(0)0R 16 , -C(0)N(R 16 )(R 17 ), -C(0)R 19 , -S(0) 2 R 19 , and -S(0) 2 N(R 16 )(R 17 ).
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, and -C(0)R 12 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from oxo,
  • Ci -6 alkyl and -C(0)R 12 .
  • -C(0)R 12 In some embodiments,
  • R 1 is a saturated monocyclic C2-7heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, hexahydropyrimidinyl, oxepanyl, thiepanyl, azapanyl, and azocanyl, wherein pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,
  • R 1 is a saturated monocyclic C2-7heterocycloalkyl selected from pyrrolidinyl, piperidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, azetidinyl, and tetrahydropyranyl.
  • R 1 is a saturated monocyclic C 2- 7heterocycloalkyl wherein the saturated monocyclic C 2- 7heterocycloalkyl is piperidine.
  • R 1 is a saturated bridged bicyclic C 2- 9heterocycloalkyl optionally substituted with one, two, three, or four R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, Ci -9 heteroaryl, - R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R
  • R 1 is a saturated bridged bicyclic C 2-9 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 ,
  • R 1 is a saturated bridged bicyclic C 2- 9 heterocycloalkyl optionally substituted with one or two R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, C 1-9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , -N(R U )C(0)
  • R 1 is a saturated bridged bicyclic C 2-9 heterocycloalkyl optionally substituted with one or two R la and each R la is independently selected from oxo, Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , - C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated bridged bicyclic C 2-9 heterocycloalkyl optionally substituted with one R la and R la is selected from
  • R 1 is an unsubstituted saturated bridged bicyclic C 2- 9 heterocycloalkyl.
  • R 1 is a saturated bridged bicyclic C2-9heterocycloalkyl substituted with one R la and R la is selected from Ci -6 alkyl, Ci.gheteroaryl, -R 14a , -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated bridged bicyclic C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)R 12 .
  • R 1 is a saturated bridged bicyclic C 2- 9heterocycloalkyl substituted with one R la and R la is - S(0) 2 R 12 .
  • R 12 is independently selected from Ci -6 alkyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl and Ci.gheteroaryl, wherein Ci -6 alkyl and Ci.gheteroaryl are optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 and each R 141 is independently selected from -OH, -NH 2 , and -N(H)CH 3 .
  • R 1 is a saturated bridged bicyclic C 2- 9heterocycloalkyl substituted with one R la and R la is -C(0)OR 9 . In some embodiments, R 1 is a saturated bridged bicyclic C 2- 9heterocycloalkyl substituted with one R la and R la is -C(0)N(R 9 )(R 10 ). In some embodiments, R 1 is a saturated bridged bicyclic C 2- 9heterocycloalkyl substituted with one R la and R la is -C(0)C(0)N(R 9 )(R 10 ). In some embodiments, R 9 is independently selected from H and Ci. 6 alkyl optionally substituted with one, two, or three R 14g . In some embodiments, R 9 is
  • R 10 is H.
  • R 1 is a saturated bridged bicyclic C 2- 9heterocycloalkyl substituted with one R la and R la is -R 14a .
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9 heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6.l0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2- 9 heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6.l0 aryl, Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci.
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- gheterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- gheterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci.
  • R 1 is a saturated bridged bicyclic C 2- 9heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated bridged bicyclic C 2-9 heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, and -C(0)R 12 .
  • R 1 is a saturated bridged bicyclic C 2- 9 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently
  • R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl optionally substituted with one, two, three, or four R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, Ce-ioaryl, Ci -9 heteroaryl, - R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )C
  • R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i0 aryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)OR 12 , -N(R u )C(0)OR 12 , -N(R u )
  • R 1 is a saturated spirocyclic C 2- 9 heterocycloalkyl optionally substituted with one or two R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S
  • R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl optionally substituted with one or two R la and each R la is independently selected from oxo, Ci -6 alkyl, Ci.gheteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated spirocyclic C2-9heterocycloalkyl optionally substituted with one R la and R la is selected from Ci -6 alkyl, Ci.
  • R 1 is an unsubstituted saturated spirocyclic C 2-9 heterocycloalkyl.
  • R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl substituted with one R la and R la is selected from C ⁇ alkyl, Ci -9 heteroaryl, -R 14a , -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)R 12 .
  • R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl substituted with one R la and R la is -S(0) 2 R 12 .
  • R 12 is independently selected from Ci -6 alkyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl and Ci -9 heteroaryl, wherein Ci -6 alkyl and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 and each R 141 is independently selected from -OH, -NH 2 , and -N(H)CH 3 .
  • R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)OR 9 . In some embodiments, R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)N(R 9 )(R 10 ). In some embodiments, R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)C(0)N(R 9 )(R 10 ). In some embodiments, R 9 is
  • R 9 is independently selected from H and unsubstituted Ci- 6 alkyl.
  • R 10 is H.
  • R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl substituted with one R la and R la is -R 14a .
  • R 14a is independently selected from Ci -6 alkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, wherein Ci.
  • Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci.
  • R 14a is independently selected from Ci -6 alkyl, C 2- gheterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2- gheterocycloalkyl, -CH 2 -C 2-g heterocycloalkyl, C 6.l0 aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci.
  • R 1 is a saturated spirocyclic C 2-g heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, Ci.gheteroaryl, -R 14a , -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated spirocyclic C 2-g heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, and -C(0)R 12 .
  • R 1 is a saturated spirocyclic C 2-g heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from oxo, Ci -6 alkyl, and -C(0)R 12 .
  • Y is -R 2 . In some embodiments, Y is -L 2 -R 2 . In some embodiments, L 2 is -CH 2 -. In some embodiments, R 2 is -C(0)0R 4 , -0C(0)N(R 4 )(R 5 ), -
  • R 2 is -C(0)0R 4 , -0C(0)N(R 4 )(R 5 ), - N(R 6 )C(0)N(R 4 )(R 5 ), -N(R 6 )C(0)0R 7 , -N(R 6 )S(0) 2 R 7 , -C(0)N(R 22 )(R 23 ), or - CH 2 C(0)N(R 24 )(R 25 ).
  • R 2 is -C(0)0R 4 .
  • R 2 is - 0C(0)N(R 4 )(R 5 ).
  • R 2 is -N(R 6 )C(0)N(R 4 )(R 5 ).
  • R 4 is selected from H, Ci -6 alkyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c .
  • R 4 is selected from H, Ci -6 alkyl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c .
  • R 5 is H.
  • R 2 is -N(R 6 )C(0)0R 7 .
  • R 2 is -N(R 6 )S(0) 2 R 7 .
  • R 7 is selected from Ci -6 alkyl, C 6- ioaryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e .
  • R 7 is selected from Ci -6 alkyl, C 6 -i 0 aryl, and Ci. 9 heteroaryl, wherein Ci -6 alkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e .
  • R 7 is Ci -6 alkyl optionally substituted with one, two, or three R 14e .
  • R 6 is H.
  • R 2 is -C(0)N(R 22 )(R 23 ).
  • R 2 is -CH 2 C(0)N(R 24 )(R 25 ).
  • R 24 is selected from H, Ci. 6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 24 is selected from H and Ci -6 alkyl optionally substituted with one, two, or three R 141 .
  • R 25 is H.
  • R 20 is H. In some embodiments, R 20 is Ci -6 alkyl. In some embodiments, R 20 is -CH 3 .
  • n 0.
  • n is 1. In some embodiments, n is 2.
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, C 3-
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ), wherein C ⁇ alkyl is optionally substituted with one, two, or three R 14b .
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , and -N(R 9 )(R 10 ).
  • n is 1 and R 3 is halogen.
  • n is 1 and R 3 is Ci- 6 alkyl.
  • the compound has the structure of Formula (la), (la’), (Iaa), (Iaa’), (lab), (lab’), (lac), (lac’), (lad), or (lad’), or a pharmaceutically acceptable salt or solvate thereof:
  • X is -0-, -S-, -S(0) 2 -, -N(R 13 )-, or -C(R 13 ) 2 -;
  • Z is H, F, or Cl
  • L 3 is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 N(H)CH 2 -, or -CH 2 N(CH 3 )CH 2 -;
  • R la is selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -0
  • each R 8 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14f , R 14g , R 14h , and R 141 are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)0R 16 , - C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), -0C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)N(R 16 )(R 17 ), - N(R 18 )C(0)0R 19 , -N(R 18 )C(0)R 19 , -N(
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • n 0, 1, 2, 3, or 4;
  • p is 0 or 1 ;
  • q 0, 1, or 2;
  • w 1 , w 2 , w 3 , and w 4 are each independently selected from 1 and 2.
  • X is -0-. In some embodiments, X is -S-. In some embodiments, X is -S(0) 2 -. In some embodiments, X is -N(R 13 )-. In some embodiments, X is -N(H)-. In some embodiments, X is -C(R 13 ) 2 -. In some embodiments, X is -CH 2 -.
  • Z is F. In some embodiments, Z is Cl. In some embodiments, Z is H.
  • L 3 is -CH 2 CH 2 -. In some embodiments, L 3 is -CH 2 CH 2 CH 2 -. In some embodiments, L 3 is -CH 2 OCH 2 -. In some embodiments, L 3 is -CH 2 N(H)CH 2 -. In some embodiments, L 3 is -CH 2 N(CH 3 )CH 2 -.
  • q is 0. In some embodiments, q is 1. In some embodiments, q is 2.
  • w 1 , w 2 , w 3 , and w 4 are each 1. In some embodiments, w 1 is 2, and w 2 , w 3 , and w 4 are each 1. In some embodiments, w 1 and w 3 are each 2, and w 2 and w 4 are each 1. In some embodiments, w 2 is 2, and w 1 , w 3 , and w 4 are each 1. In some embodiments, w 1 and w 2 are each 2, and w 3 and w 4 are each 1. [0096] In some embodiments, p is 1. In some embodiments, p is 0.
  • R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C2-9heterocycloalkyl, C 6 - l oaryl, Ci.gheteroaryl, -R 14a , -OR 8 , -SR 8 , - N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 ,
  • R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R
  • R la is selected from Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), - C(0)R 12 , and -S(0) 2 R 12 .
  • R la is -C(0)R 12 .
  • R la is - S(0) 2 R 12 .
  • R 12 is independently selected from Ci -6 alkyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C3 -6 cycloalkyl, C 2- gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl and Ci.gheteroaryl, wherein Ci -6 alkyl and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 and each R 141 is independently selected from -OH, -NH 2 , and -N(H)CH 3 . In some embodiments, R la is -C(0)OR 9 . In some embodiments, R la is - C(0)N(R 9 )(R 10 ). In some embodiments, R la is -C(0)C(0)N(R 9 )(R 10 ).
  • R 9 is independently selected from H and Ci -6 alkyl optionally substituted with one, two, or three R 14g . In some embodiments, R 9 is independently selected from H and unsubstituted Ci- 6 alkyl. In some embodiments, R 10 is H. In some embodiments, R la is -R 14a .
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.
  • gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, -OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)OR 16 , -C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), -0C(0)N(R 16 )(R 17 ), - N(R 18 )C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)0R 19 , -N(R 18 )C(0)R 19 , -N(R 18 )S(0) 2 R 19 , -C(0)R 19 , - S(0) 2 R 19 , -S(0) 2 N(R 16 )(R 17 ), and -OC(0)
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -
  • R 20 is H. In some embodiments, R 20 is Ci- 6 alkyl. In some embodiments, R 20 is -CH 3 .
  • n 0.
  • n is 1. In some embodiments, n is 2.
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -OC(0)R 12 , wherein Ci -6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ), wherein C ⁇ alkyl is optionally substituted with one, two, or three R 14b .
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , and -N(R 9 )(R 10 ).
  • n is 1 and R 3 is halogen.
  • n is 1 and R 3 is Ci -6 alkyl.
  • the compound has the structure of Formula (Iae) or (Iae’), or a pharmaceutically acceptable salt or solvate thereof:
  • X is -0-, -S-, -S(0) 2 -, -N(R 13 )-, or -C(R 13 ) 2 -;
  • R 1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, -R 14a , -OR 8 , - SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C2 -6 alkenyl, C2 -6 alkynyl, C 3- 6 cycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10
  • each R 8 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C2 -6 alkenyl, C2- 6alkynyl, C 3-6C ycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C2 -6 alkenyl, C2- 6alkynyl, C 3-6C ycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C2 -6 alkenyl, C2 -6 alkynyl, C 3-6C ycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14f , R 14g , R 14h , and R 141 are each independently selected from halogen, -CN, Ci -6 alkyl, C2 -6 alkenyl, C2 -6 alkynyl, C 3-6C ycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)0R 16 , - C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), -0C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)N(R 16 )(R 17 ), - N(R 18 )C(0)0R 19 , -N(R 18 )C(0)R 19
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2- 9heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • n 0, 1, 2, 3, or 4;
  • p 0 or 1.
  • X is -0-. In some embodiments, X is -S-. In some embodiments, X is -S(0) 2 -. In some embodiments, X is -N(R 13 )-. In some embodiments, X is -N(H)-. In some embodiments, X is -C(R 13 ) 2 -. In some embodiments, X is -CH 2 -.
  • Z is F. In some embodiments, Z is Cl. In some embodiments, Z is H.
  • p is 1. In some embodiments, p is 0.
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, and -C(0)R 12 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from oxo, Ci -6 alkyl, and -C(0)R 12 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from oxo and Ci- 6 alkyl.
  • R 20 is H. In some embodiments, R 20 is Ci- 6 alkyl. In some embodiments, R 20 is -CH 3 .
  • n 0.
  • n is 1. In some embodiments, n is 2.
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, C 3 .
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ), wherein Ci -6 alkyl is optionally substituted with one, two, or three R 14b .
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , and -N(R 9 )(R 10 ).
  • n is 1 and R 3 is halogen.
  • n is 1 and R 3 is Ci -6 alkyl.
  • the compound has the structure of Formula (lb), (lb’), (Iba), (Iba’), (Ibb), (Ibb’), (Ibc), (Ibc’), (Ibd), or (Ibd’), or a pharmaceutically acceptable salt or solvate thereof:
  • L 3 is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 N(H)CH 2 -, or -CH 2 N(CH 3 )CH 2 -;
  • R la is selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -
  • R 8 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • R 9 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ;
  • R 10 is selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three
  • R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • R 12 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 14a , R 14f , R 14g , R 14h , and R 141 are each independently selected from halogen, -CN, Ci.
  • 6cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, -OR 15 , -SR 15 , - N(R 16 )(R 17 ), -C(0)0R 16 , -C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), -0C(0)N(R 16 )(R 17 ), - N(R 18 )C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)0R 19 , -N(R 18 )C(0)R 19 , -N(R 18 )
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • q 0, 1, or 2;
  • w 1 , w 2 , w 3 , and w 4 are each independently selected from 1 and 2.
  • L 3 is -CH 2 CH 2 -. In some embodiments, L 3 is -CH 2 CH 2 CH 2 -. In some embodiments, L 3 is -CH 2 OCH 2 -. In some embodiments, L 3 is -CH 2 N(H)CH 2 -. In some embodiments, L 3 is -CH 2 N(CH 3 )CH 2 -.
  • q is 0. In some embodiments, q is 1. In some embodiments, q is 2.
  • w 1 , w 2 , w 3 , and w 4 are each 1.
  • w 1 is 2, and w 2 , w 3 , and w 4 are each 1.
  • w 1 and w 3 are each 2, and w 2 and w 4 are each 1.
  • w 2 is 2, and w 1 , w 3 , and w 4 are each 1.
  • w 1 and w 2 are each 2, and w 3 and w 4 are each 1.
  • R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 - l oaryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , - N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 , -N(R U
  • R la is independently selected from halogen, oxo, Ci -6 alkyl, Ci -6 haloalkyl, C 2-9 heterocycloalkyl, Ci -9 heteroaryl, -R 14a , -OR 8 , - C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R la is independently selected from halogen, oxo, Ci -6 alkyl, Ci -6 haloalkyl, C 2-9 heterocycloalkyl, Ci -9 heteroaryl, -R 14a , -OR 8 , - C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R la is selected from Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R la is -C(0)R 12 .
  • R la is -S(0) 2 R 12 .
  • R 12 is independently selected from Ci.
  • R 12 is independently selected from Ci -6 alkyl and Ci. 9 heteroaryl, wherein Ci -6 alkyl and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 and each R 141 is independently selected from - OH, -NH 2 , and -N(H)CH 3 . In some embodiments, R la is -C(0)0R 9 . In some embodiments, R la is - C(0)N(R 9 )(R 10 ). In some embodiments, R la is -C(0)C(0)N(R 9 )(R 10 ).
  • R 9 is independently selected from H and Ci -6 alkyl optionally substituted with one, two, or three R 14g . In some embodiments, R 9 is independently selected from H and unsubstituted Ci- 6 alkyl. In some embodiments, R 10 is H. In some embodiments, R la is -R 14a .
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.
  • gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, -OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)0R 16 , -C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), -0C(0)N(R 16 )(R 17 ), - N(R 18 )C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)0R 19 , -N(R 18 )C(0)R 19 , -N(R 18 )S(0) 2 R 19 , -C(0)R 19 , - S(0) 2 R 19 , -S(0) 2 N(R 16 )(R 17 ), and -0
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6.l0 aryl, Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, - CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, -OR 15 , -N(R 16 )(R 17 ), -C(0)0R 16 , - C(0)N(R 16 )(R 17 ), -C(0)R 19 , -S(0) 2 R 19 , and -S(0) 2 N(R 16
  • the compound has the structure of Formula (Ibe) or (Ibe’), or a pharmaceutically acceptable salt or solvate thereof:
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci_ 9 heteroaryl, -R 14a , -OR 8 , - SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , -
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2.6 alkenyl, C 2-6 alkynyl, C 3.6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 14a , R 14g , R 14h , and R 141 are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-i0 aryl, Ci -9 heteroaryl, -OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)0R 16 , -C(0)N(R 16 )(R 17 ), - C(0)C(0)N(R 16 )(R 17 ), -0C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)0R 19 , - N(R 18 )C(0)R 19 , -N(R 18 )S(0) 2 R 19
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl; and each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl.
  • R 1 is a saturated monocyclic C 2- 7heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, and -C(0)R 12 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from oxo, Ci -6 alkyl, and -C(0)R 12 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from oxo
  • Ci -6 alkyl In some embodiments,
  • the compound has the structure of Formula (Ic) or (Ic’), or a pharmaceutically acceptable salt or solvate thereof:
  • X is -0-, -S-, -S(0) 2 -, -N(R 13 )-, or -C(R 13 ) 2 -;
  • Z is H, F, or Cl
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl,
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -0C(0)R
  • each R 8 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14f , R 14g , R 14h , and R 141 are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- gheterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)0R 16 , - C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), -0C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)N(R 16 )(R 17 ), - N(R 18 )C(0)0R 19 , -N(R 18 )C(0)R 19
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2- 9heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • n 0, 1, 2, 3, or 4;
  • p 0 or 1.
  • X is -0-. In some embodiments, X is -S-. In some embodiments, X is -S(0) 2 -. In some embodiments, X is -N(R 13 )-. In some embodiments, X is -N(H)-. In some embodiments, X is -C(R 13 ) 2 -. In some embodiments, X is -CH 2 -.
  • Z is F. In some embodiments, Z is Cl. In some embodiments, Z is H. [00123] In some embodiments, p is 1. In some embodiments, p is 0.
  • each R lb is independently selected from H, halogen, -CN, Ci. 6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, R 14a , -OR 8 , - SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 ,
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 - l oaryl, Ci -9 heteroaryl, R 14a , -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ).
  • each R lb is independently selected from H, Ci -6 alkyl, C3 -6 cycloalkyl, and R 14a . In some embodiments, each R lb is independently selected from H, Ci. 6 alkyl, and C3-6cycloalkyl. In some embodiments, each R lb is independently selected from H and Ci- 6 alkyl. In some embodiments, each R lb is -CH 3 . In some embodiments, each R lb is
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9 heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6.l0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2- gheterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci.
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci.
  • R 20 is H. In some embodiments, R 20 is Ci -6 alkyl. In some embodiments, R 20 is -CH 3 .
  • n 0.
  • n is 1. In some embodiments, n is 2.
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, C 3- 6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -OC(0)R 12 , wherein Ci -6 alkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , - C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ), wherein Ci -6 alkyl is optionally substituted with one, two, or three R 14b .
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , and -N(R 9 )(R 10 ).
  • n is 1 and R 3 is halogen.
  • n is 1 and R 3 is Ci -6 alkyl.
  • the compound has the structure of Formula (Id) or (Id’), or a pharmaceutically acceptable salt or solvate thereof:
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- i0 aryl, Ci -9 heteroaryl, R 14a , -OR 8 , -SR 8 , - N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , - S(0)R 12
  • R 8 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • R 9 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ; R 10 is selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the nitrogen to which they are attached, form a C 2- 9heterocycloalkyl ring optionally substituted with one, two, or three
  • R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • R 12 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 14a , R 14f , R 14g , R 14h , and R 141 are each independently selected from halogen, -CN, Ci.
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl.
  • each R lb is independently selected from H, halogen, -CN, Ci. 6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, R 14a , -OR 8 , - SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , -C
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6- l oaryl, Ci -9 heteroaryl, R 14a , -OR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ).
  • each R lb is independently selected from H, Ci -6 alkyl, C3-6cycloalkyl, and R 14a . In some embodiments, each R lb is independently selected from H, Ci. 6 alkyl, and C3 -6 cycloalkyl. In some embodiments, each R lb is independently selected from H and Ci -6 alkyl. In some embodiments, each R lb is -CH 3 . In some embodiments, each R lb is
  • R 14a is independently selected from Ci -6 alkyl, C 2- gheterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- gheterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6.l0 aryl, Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci.
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- gheterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- gheterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci.
  • the compound has the structure of Formula (Ie) or (Ie’), or a pharmaceutically acceptable salt or solvate thereof:
  • X is -0-, -S-, -S(0) 2 -, -N(R 13 )-, or -C(R 13 ) 2 -;
  • Z is H, F, or Cl
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl,
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, Ci -9 heteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -0C(0)R
  • each R 8 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14f , R 14g , R 14h , and R 141 are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- gheterocycloalkyl, C 6-i0 aryl, Ci -9 heteroaryl, -OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)0R 16 , - C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), -0C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)N(R 16 )(R 17 ), - N(R 18 )C(0)0R 19 , -N(R 18 )C(0)R 19 ,
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- gheterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • n 0, 1, 2, 3, or 4;
  • p 0 or 1.
  • X is -0-. In some embodiments, X is -S-. In some embodiments, X is -S(0) 2 -. In some embodiments, X is -N(R 13 )-. In some embodiments, X is -N(H)-. In some embodiments, X is -C(R 13 ) 2 -. In some embodiments, X is -CH 2 -.
  • Z is F. In some embodiments, Z is Cl. In some embodiments, Z is H.
  • p is 1. In some embodiments, p is 0.
  • each R lb is independently selected from H, halogen, -CN, Ci. 6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, R 14a , -OR 8 , - SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6C ycloalkyl, C 2-9 heterocycloalkyl, C 6 - 14a , -OR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , n some embodiments, each R lb is independently selected from H, Ci -6 alkyl, . In some embodiments, each R lb is independently selected from H, Ci. 6 alkyl, and C3-6cycloalkyl. In some embodiments, each R lb is independently selected from H and Ci -6 alkyl. In some embodiments, each R lb is -CH 3 . In some embodiments, each R lb is
  • R 14a is independently selected from Ci -6 alkyl, C 2- gheterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- gheterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci.
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- gheterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci.
  • R 20 is H.
  • R 20 is Ci -6 alkyl.
  • R 20 is -CH 3 .
  • n 0.
  • n is 1. In some embodiments, n is 2.
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, C 3- 6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -OC(0)R 12 , wherein Ci -6 alkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ), wherein Ci -6 alkyl is optionally substituted with one, two, or three R 14b .
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , and -N(R 9 )(R 10 ).
  • n is 1 and R 3 is halogen.
  • n is 1 and R 3 is Ci- 6 alkyl.
  • the compound has the structure of Formula (If) or (If), or a pharmaceutically acceptable salt or solvate thereof:
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 - l oaryl, Ci.gheteroaryl, R 14a , -OR 8 , -SR 8 , - N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12
  • R 8 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • R 9 is selected from H, Ci -6 alkyl, C 2.6 alkenyl, C 2.6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14g ;
  • R 10 is selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the nitrogen to which they are attached, form a C 2- 9heterocycloalkyl ring optionally substituted with one, two, or three
  • R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • R 12 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 141 ; each R 14a , R 14f , R 14g , R 14h , and R 141 are each independently selected from halogen, -CN, Ci.
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- gheterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl.
  • each R lb is independently selected from H, halogen, -CN, Ci. 6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, R 14a , -OR 8 , - SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 - l oaryl, Ci -9 heteroaryl, R 14a , -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ).
  • each R lb is independently selected from H, Ci -6 alkyl, C 3-6 cycloalkyl, and R 14a . In some embodiments, each R lb is independently selected from H, Ci. 6 alkyl, and C 3-6C ycloalkyl. In some embodiments, each R lb is independently selected from H and Ci- 6 alkyl. In some embodiments, each R lb is -CH 3 . In some embodiments, each R lb is
  • R 14a is independently selected from Ci -6 alkyl, C 2- gheterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C 6-l0 aryl, Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci.
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C2- gheterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C2-9heterocycloalkyl, -CH 2 -C2- gheterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci.
  • SSAO inhibitors and uses thereof.
  • described herein is a compound that has the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
  • Z is H, F, or Cl
  • L 2 is Ci -6 alkyl
  • R 1 is C 2-6 alkenyl, C 2-6 alkynyl, C 2- 9heterocycloalkyl, or Ci -9 heteroaryl, wherein C 2-6 alkenyl, C 2- 6 alkynyl, C2-9heterocycloalkyl, or Ci.gheteroaryl are optionally substituted with one, two, three, four, or five R la ;
  • each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-i oaryl, Ci.gheteroaryl, -R 14a , - OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , - N(R U )S(0) 2 R 12 , -C(0)R 12 ,
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -0
  • R 4 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c ;
  • R 5 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R 4 and R 5 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14d ;
  • R 6 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl
  • R 7 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 - l 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e ;
  • each R 8 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14c , R 14d , R 14e , R 14f , R 14g , R 14h , R 14i , R 14j , R 14k , R 141 , R 14m , and R 14n are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, - OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)0R 16 , -C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), - 0C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)
  • 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci.
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6C ycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6C ycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • R 21 is selected from H and Ci -6 alkyl
  • R 22 is selected from Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci. 9heteroaryl are optionally substituted with one, two, or three R 14j ; R 23 is selected from H and Ci -6 alkyl; or R 22 and R 23 together with the nitrogen to which they are attached, form a C 2- 9heterocycloalkyl ring optionally substituted with one, two, or three
  • R 24 is selected from H, Ci -6 alkyl, C2 -6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • R is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R and R together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14m ;
  • R 26 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14n ;
  • n 0, 1, 2, 3, or 4;
  • p 0 or 1.
  • substituents are selected from among a subset of the listed alternatives.
  • X is -0-, -S-, -S(0) 2 -, -N(R 13 )-, or -C(R 13 ) 2 -.
  • X is -0-.
  • X is -S-.
  • X is - S(0) 2 -.
  • X is -N(R 13 )-.
  • X is -N(H)-.
  • X is -C(R 13 ) 2 -.
  • X is -CH 2 -.
  • Z is H, F, or Cl. In some embodiments, Z is F. In some embodiments,
  • Z is Cl. In some embodiments, Z is H.
  • p is 1. In some embodiments, p is 0.
  • Y is -R 1 . In some embodiments, Y is -I ⁇ -R 1 . In some embodiments,
  • Y is -L 2 -R ⁇ In some embodiments, Y is I ⁇ -L ⁇ R 1 . In some embodiments, Y is -L 2 - I ⁇ -R 1 . In some embodiments, L 2 is -CH 2 -.
  • R 1 is C 2-6 alkynyl, C 2- 9 heterocycloalkyl, or Ci -9 heteroaryl, wherein C 2-6 alkynyl, C 2-9 heterocycloalkyl, or Ci -9 heteroaryl are optionally substituted with one, two, three, or four R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, C 1-9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(
  • R 1 is C 2- 6 alkynyl, C 2-9 heterocycloalkyl, or Ci -9 heteroaryl, wherein C 2-6 alkynyl, C 2-9 heterocycloalkyl, or Ci. gheteroaryl are optionally substituted with one, two, or three R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 .
  • R 1 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is
  • R 1 is C 2-9 heterocycloalkyl optionally substituted with one or two R la and each R la is independently selected from oxo, Ci. ealkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and - S(0) 2 R 12 .
  • R 1 is C 2-9 heterocycloalkyl optionally substituted with one R la and R la is selected from Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is unsubstituted C 2- gheterocycloalkyl.
  • R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is selected from C ⁇ alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), - C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)R 12 .
  • R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is -S(0) 2 R 12 .
  • R 12 is independently selected from Ci -6 alkyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 3-6C ycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl and Ci -9 heteroaryl, wherein Ci -6 alkyl and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 and each R 141 is independently selected from -OH, -NH 2 , and -N(H)CH 3 . In some embodiments, R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)0R 9 . In some embodiments, R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is - C(0)N(R 9 )(R 10 ).
  • R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)C(0)N(R 9 )(R 10 ).
  • R 9 is independently selected from H and Ci -6 alkyl optionally substituted with one, two, or three R 14g .
  • R 9 is independently selected from H and unsubstituted Ci -6 alkyl.
  • R 10 is H.
  • R 1 is C 2- 9heterocycloalkyl substituted with one R la and R la is -R 14a .
  • R 14a is independently selected from Ci -6 alkyl, C2-9heterocycloalkyl, -CH 2 -C 2- gheterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci.
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.
  • gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, -OR 15 , -N(R 16 )(R 17 ), - C(0)0R 16 , -C(0)N(R 16 )(R 17 ), -C(0)R 19 , -S(0) 2 R 19 , and -S(0) 2 N(R 16 )(R 17 ).
  • R 1 is C 2- 9heterocycloalkyl wherein C 2- 9heterocycloalkyl is piperidine.
  • R 1 is Ci -9 heteroaryl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3- 6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)OR 12 , -N(R u )C(0)OR 12 , -
  • R 1 is Ci -9 heteroaryl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, -R 14a , -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ).
  • Y is -R 2 . In some embodiments, Y is -L 2 -R 2 . In some embodiments, Y is -L 2 -R 2 . In some
  • L 2 is -CH 2 -.
  • R 2 is -C(0)OR 4 , -0C(0)N(R 4 )(R 5 ), - N(R 6 )C(0)N(R 4 )(R 5 ), -N(R 6 )C(0)0R 7 , -N(R 6 )S(0) 2 R 7 , -C(0)N(R 22 )(R 23 ), or - CH 2 C(0)N(R 24 )(R 25 ).
  • R 2 is -C(0)OR 4 .
  • R 2 is - 0C(0)N(R 4 )(R 5 ).
  • R 2 is -N(R 6 )C(0)N(R 4 )(R 5 ).
  • R 4 is selected from H, Ci -6 alkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c .
  • R 4 is selected from H, Ci -6 alkyl, and Ci.gheteroaryl, wherein Ci -6 alkyl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c .
  • R 5 is H.
  • R 2 is -N(R 6 )C(0)0R 7 .
  • R 2 is -N(R 6 )S(0) 2 R 7 .
  • R 7 is selected from Ci -6 alkyl, C 6- l0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e .
  • R 7 is selected from Ci -6 alkyl, C 6 -i 0 aryl, and Ci.
  • Ci -6 alkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e .
  • R 7 is Ci -6 alkyl optionally substituted with one, two, or three R 14e .
  • R 6 is H.
  • R 2 is -C(0)N(R 22 )(R 23 ).
  • R 2 is -CH 2 C(0)N(R 24 )(R 25 ).
  • R 24 is selected from H, Ci.
  • R 24 is selected from H and Ci -6 alkyl optionally substituted with one, two, or three R 141 .
  • R 25 is H.
  • R 20 is H. In some embodiments, R 20 is Ci- 6 alkyl. In some embodiments, R 20 is -CH 3 .
  • n 0.
  • n is 1. In some embodiments, n is 2.
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, C3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -OC(0)R 12 , wherein Ci -6 alkyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ), wherein C ⁇ alkyl is optionally substituted with one, two, or three R 14b .
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , and -N(R 9 )(R 10 ).
  • n is 1 and R 3 is halogen.
  • n is 1 and R 3 is Ci -6 alkyl.
  • R 1 is C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, or Ci -9 heteroaryl, wherein C 2-6 alkenyl, C 2- 6 alkynyl, C 2-9 heterocycloalkyl, or Ci -9 heteroaryl are optionally substituted with one, two, three, four, or five R la ;
  • each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -0C(0)R
  • R 4 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c ;
  • R 5 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R 4 and R 5 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14d ;
  • R 6 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl
  • R 7 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 - ioaryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - 9heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e ;
  • each R 8 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2 - 6alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2 - 6alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14c , R 14d , R 14e , R 14f , R 14g , R 14h , R 14i , R 14j , R 14k , R 141 , R 14m , and R 14n are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 .
  • l 0 aryl, -CH 2 -C 6-i oaryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci.
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • R 21 is selected from H and Ci -6 alkyl
  • R 22 is selected from Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci. 9heteroaryl are optionally substituted with one, two, or three R 14j ;
  • R 23 is selected from H and Ci -6 alkyl; or R 22 and R 23 together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14k ;
  • R 24 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • R is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R and R together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14m ;
  • R 26 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14n ;
  • n 0, 1, 2, 3, or 4;
  • p 0 or 1.
  • X is -0-, -S-, -S(0) 2 -, -N(R 13 )-, or -C(R 13 ) 2 -. In some embodiments, X is -0-. In some embodiments, X is -S-. In some embodiments, X is -S(0) 2 -. In some
  • X is -N(R 13 )-. In some embodiments, X is -N(H)-. In some embodiments, X is - C(R 13 ) 2 -. In some embodiments, X is -CH 2 -.
  • Z is Cl. In some embodiments, Z is H.
  • p is 1. In some embodiments, p is 0.
  • Y is -R 1 . In some embodiments, Y is -I ⁇ -R 1 . In some embodiments,
  • Y is -L 2 -R ⁇ In some embodiments, Y is I ⁇ -L ⁇ R 1 . In some embodiments, Y is -L 2 - I ⁇ -R 1 . In some embodiments, L 2 is -CH 2 -.
  • R 1 is C 2-6 alkynyl, C 2- gheterocycloalkyl, or Ci.gheteroaryl, wherein C 2-6 alkynyl, C 2- 9heterocycloalkyl, or Ci.gheteroaryl are optionally substituted with one, two, three, or four R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R
  • R 1 is C 2- 6 alkynyl, C 2- 9heterocycloalkyl, or Ci -9 heteroaryl, wherein C 2-6 alkynyl, C 2- 9heterocycloalkyl, or Ci. 9 heteroaryl are optionally substituted with one, two, or three R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6- l oaryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)
  • R 1 is C 2- 9heterocycloalkyl optionally substituted with one or two R la and each R la is independently selected from oxo, Ci. ealkyl, Ci -9 heteroaryl, -R 14a , -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and - S(0) 2 R 12 .
  • R 1 is C 2- 9heterocycloalkyl optionally substituted with one R la and R la is selected from C ⁇ alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is unsubstituted C 2- gheterocycloalkyl.
  • R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is selected from C ⁇ alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), - C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)R 12 .
  • R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is -S(0) 2 R 12 .
  • R 12 is independently selected from Ci -6 alkyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl and Ci -9 heteroaryl, wherein Ci -6 alkyl and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 and each R 141 is independently selected from -OH, -NH 2 , and -N(H)CH 3 . In some embodiments, R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)0R 9 . In some embodiments, R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is - C(0)N(R 9 )(R 10 ).
  • R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)C(0)N(R 9 )(R 10 ).
  • R 9 is independently selected from H and Ci -6 alkyl optionally substituted with one, two, or three R 14g .
  • R 9 is independently selected from H and unsubstituted Ci -6 alkyl.
  • R 10 is H. In some embodiments
  • R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is -R 14a .
  • R 14a is independently selected from Ci -6 alkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci.
  • R 14a is independently selected from Ci -6 alkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci.
  • heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, -OR 15 , -N(R 16 )(R 17 ), - C(0)0R 16 , -C(0)N(R 16 )(R 17 ), -C(0)R 19 , -S(0) 2 R 19 , and -S(0) 2 N(R 16 )(R 17 ).
  • R 1 is C 2- 9heterocycloalkyl wherein C 2- 9heterocycloalkyl is piperidine.
  • R 1 is Ci_ 9 heteroaryl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3- 6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)OR 12 , -N(R u )C(0)OR 12 , -
  • R 1 is Ci -9 heteroaryl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, -R 14a , -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ).
  • Y is -R 2 . In some embodiments, Y is -L 2 -R 2 . In some embodiments, Y is -L 2 -R 2 . In some
  • L 2 is -CH 2 -.
  • R 2 is -C(0)OR 4 , -0C(0)N(R 4 )(R 5 ), - N(R 6 )C(0)N(R 4 )(R 5 ), -N(R 6 )C(0)0R 7 , -N(R 6 )S(0) 2 R 7 , -C(0)N(R 22 )(R 23 ), or - CH 2 C(0)N(R 24 )(R 25 ).
  • R 2 is -C(0)OR 4 .
  • R 2 is - 0C(0)N(R 4 )(R 5 ).
  • R 2 is -N(R 6 )C(0)N(R 4 )(R 5 ).
  • R 4 is selected from H, Ci -6 alkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 3-6C ycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14c .
  • R 4 is selected from H, Ci -6 alkyl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c .
  • R 5 is H.
  • R 2 is -N(R 6 )C(0)0R 7 .
  • R 2 is -N(R 6 )S(0) 2 R 7 .
  • R 7 is selected from Ci -6 alkyl, C 6 - ! oaryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14e .
  • R 7 is selected from Ci -6 alkyl, C 6.l0 aryl, and Ci.
  • Ci -6 alkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e .
  • R 7 is Ci -6 alkyl optionally substituted with one, two, or three R 14e .
  • R 6 is H.
  • R 2 is -C(0)N(R 22 )(R 23 ).
  • R 2 is -CH 2 C(0)N(R 24 )(R 25 ).
  • R 24 is selected from H, Ci.
  • R 24 is selected from H and Ci -6 alkyl optionally substituted with one, two, or three R 141 .
  • R 25 is H.
  • R 20 is H. In some embodiments, R 20 is Ci- 6 alkyl. In some embodiments, R 20 is -CH 3 .
  • n 0.
  • n is 1. In some embodiments, n is 2.
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, C 3- 6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -OC(0)R 12 , wherein Ci -6 alkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ), wherein C ⁇ alkyl is optionally substituted with one, two, or three R 14b .
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , and -N(R 9 )(R 10 ).
  • n is 1 and R 3 is halogen.
  • n is 1 and R 3 is Ci -6 alkyl.
  • compounds described herein include, but are not limited to, those described in Table 1.
  • provided herein is a pharmaceutically acceptable salt or solvate of a compound that is described in Table 1.
  • compounds described herein include, but are not limited to, those described in Table 2. TABLE 2
  • compounds described herein are in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term“pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation.
  • Handbook of Pharmaceutical Salts Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G.
  • Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms.
  • solubility often is a function of pH
  • selective dissolution in one or another part of the digestive tract is possible, and this capability can be manipulated as one aspect of delayed and sustained release behaviors.
  • the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid to provide a "pharmaceutically acceptable acid addition salt.”
  • the compound described herein i.e. free base form
  • the compound described herein is basic and is reacted with an organic acid or an inorganic acid.
  • Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and
  • Organic acids include, but are not limited to, l-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L);
  • benzenesulfonic acid benzoic acid; camphoric acid (+); camphor- lO-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecyl sulfuric acid; ethane-l,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid;
  • hippuric acid isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene- 1, 5 -di sulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid ⁇ p ); and undecylenic acid.
  • a compound described herein is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base to provide a "pharmaceutically acceptable base addition salt.”
  • the compound described herein is acidic and is reacted with a base.
  • an acidic proton of the compound described herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion.
  • compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine.
  • compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like.
  • Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like.
  • the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of isolating or purifying the compound with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • Solvates of compounds described herein are conveniently prepared or formed during the processes described herein.
  • the compounds provided herein optionally exist in unsolvated as well as solvated forms.
  • sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway.
  • the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.
  • the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of
  • Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be
  • incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 35 S, 18 F, 36 Cl.
  • isotopically-labeled compounds described herein for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half- life or reduced dosage requirements.
  • one or more hydrogen atoms of the compounds described herein is replaced with deuterium.
  • the compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration.
  • the compounds presented herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • E
  • Z
  • isomers as well as the appropriate mixtures thereof.
  • stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns.
  • compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomers.
  • resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • separation of steroisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof.
  • stereoisomers are obtained by stereoselective synthesis.
  • prodrugs refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not.
  • the prodrug may be a substrate for a transporter. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility.
  • An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the“prodrug”) but then is metabolically hydrolyzed to provide the active entity.
  • a further example of a prodrug is a short peptide
  • a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al ., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard,
  • a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester,
  • a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group.
  • a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group.
  • compounds described herein are prepared as alkyl ester prodrugs.
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound described herein as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds is a prodrug for another derivative or active compound.
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound described herein as set forth herein are included within the scope of the claims.
  • some of the herein-described compounds is a prodrug for another derivative or active compound.
  • a prodrug of the compound disclosed herein permits targeted delivery of the compound to a particular region of the gastrointestinal tract.
  • a prodrug is formed by the formation of a covalent linkage between drug and a carrier in such a manner that upon oral administration the moiety remains intact in the stomach and small intestine.
  • This approach involves the formation of prodrug, which is a pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation in the biological environment to release the active drug.
  • Formation of prodrugs has improved delivery properties over the parent drug molecule.
  • the problem of stability of certain drugs from the adverse environment of the upper gastrointestinal tract can be eliminated by prodrug formation, which is converted into parent drug molecule once it reaches into the colon.
  • Site specific drug delivery through site specific prodrug activation may be accomplished by the utilization of some specific property at the target site, such as altered pH or high activity of certain enzymes relative to the non-target tissues for the prodrug-drug conversion.
  • conjugate conjugates include, but are not limited to, azo bond conjugates, glycoside conjugates, glucuronide conjugates, cyclodextrin conjugates, dextran conjugates or amino-acid conjugates.
  • the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
  • A“metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
  • the term“active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • the term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups.
  • Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
  • the compounds described herein are rapidly metabolized following absorption from the gastro-intestinal tract to metabolites that have greatly reduced SSAO inhibitor activity.
  • the compounds are rapidly metabolized in plasma.
  • the compounds are rapidly metabolized by the intestines.
  • the compounds are rapidly metabolized by the liver.
  • intermediate 1-1 is reacted to incorporate a suitable amine protecting group.
  • a suitable protecting group is a Boc group to provide intermediate 1-2.
  • suitable conditions include the use of Boc 2 0 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the base is an organic base such as triethylamine.
  • the appropriate solvent is an alcohol solvent such as methanol.
  • the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
  • 1-2 is subjected to suitable conditions to incorporate a primary alcohol protecting group.
  • a suitable protecting group is a silyl protecting group such as /-butyldimethyl silyl (TBS) to provide intermediate 1-3.
  • conditions include the use an appropriate reagent such as TBS-C1 using an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base is imidazole.
  • the appropriate solvent is a chlorinated solvent such as dichloromethane.
  • the suitable temperature is about 0 °C to room temperature and the appropriate amount of time is about 18 hours (overnight).
  • 1-3 is reacted under suitable oxidization conditions to provide intermediate 1-4.
  • the alcohol is oxidized under Swem oxidation conditions using an appropriate reagent such as oxalyl chloride with an appropriate base in an appropriate solvent or solvent mixture at an appropriate temperature and an appropriate amount of time.
  • the appropriate base is an organic base such as triethylamine.
  • the appropriate the solvent is a chlorinated solvent such as dichloromethane.
  • the suitable temperature is about -78 °C to room temperature and the appropriate amount of time is about 2 to 18 hours (overnight).
  • suitable one carbon-homologation conditions include the use of phosphonium reagents.
  • suitable one-carbon-homologation conditions includes pre-treating either (fluoromethyl)triphenylphosphonium bromide or tetrafluorob orate salt with an appropriate base, with an appropriate solvent for an appropriate amount of time at an appropriate temperature before the addition of 1-4.
  • the appropriate base is NaHMDS.
  • the appropriate solvent is an ethereal solvent such as THF.
  • the appropriate temperature and amount of time before addition to 1-4 is about 30 mins at about -20 °C. In some embodiments, after 1-4 is added the reaction is continued for an additional about 2 to 18 hours (overnight) at about room temperature.
  • 1-5 was isolated as mixture of regioisomers. In some embodiments, the regioisomers of 1-5 were separated by flash chromatography under appropriate conditions. In some embodiments, appropriate conditions for separation of the regioisomers was flash chromatography using silica gel, eluting with an appropriate solvent system such as a mixture of hexanes and ethyl acetate.
  • 1-5 is reacted under suitable conditions to remove the alcohol protecting group to provide intermediate 1-6.
  • appropriate conditions include using tetrabutylammonium fluoride in a suitable solvent at an appropriate temperature and amount of time.
  • the appropriate solvent is an ethereal solvent such as THF.
  • the appropriate temperature and time is about 1 to 18 hour (overnight) at about room temperature.
  • further purification via flash chromatography using an appropriate solvent system provide the pure E- or Z-isomers of 1-6.
  • appropriate conditions for separation of the regioisomers was flash chromatography using silica gel, eluting with an appropriate solvent system such as a mixture of hexanes and ethyl acetate.
  • 1-6 is reacted under suitable conditions to provide intermediate 1-7.
  • appropriate conditions include using methanesulfonyl chloride using an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base is an organic base such as triethylamine.
  • the appropriate solvent is acetone.
  • the appropriate temperature and time is about 0 °C and about lh.
  • the reaction mixture is filtered and the filtrate is used directly as a solution of intermediate 1-7 in acetone.
  • 1-7 is reacted under suitable conditions to provide intermediate bromide 1-8.
  • appropriate conditions include using lithium bromide in an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate solvent is acetone.
  • the appropriate temperature and time is about room temperature and about lh.
  • 1-8 is reacted with intermediate 1-9 under suitable conditions to provide intermediate 1-10.
  • 1-9 is 4-(pyrimidin-2-yl)phenol, 4-(pyridin-2- yl)phenol or 4-(lH-pyrazol-l-yl)phenol.
  • 1-9 is 4-(lH-tetrazol-5-yl)phenol, 4- (3-methyl-l,2,4-oxadiazol-5-yl)phenol, 4-(3-isopropyl-l,2,4-oxadiazol-5-yl)phenol, 4-(l -ethyl- 1H- tetrazol-5-yl)-phenol, 4-(5-methyl-l,3,4-oxadiazol-2-yl)phenol, 4-(5-amino-lH-l,2,4-triazol-3- yl)phenol, 4-(5-methyl-l,2,4-oxadiazol-3-yl)phenol, 4-(5-amino-l,3,4-oxadiazol-2-yl)phenol, 4- oxazol-2-yl-phenol, 4-(l,3,4-oxadiazol-2-yl)phenol, 4-(3,5-dimethyl-lH-pyrazol-4-yl)phenol, 4- (lH-pyrazol-4-yl)phenol
  • 1-9 is tert-butyl 4-(4- hydroxyphenyl)piperidine-l-carboxylate, tert-butyl 3-(4-hydroxyphenyl)pyrrolidine-l-carboxylate or tert-butyl 3-(4-hydroxyphenyl)azetidine-l-carboxylate.
  • 1-9 is 2-(4- hydroxyphenyl)-N-isopropyloxazole-4-carboxamide, 4-(3,5-dimethylisoxazol-4-yl)phenol, 4-(3- amino-5-methylisoxazol-4-yl)phenol, 5-(4-hydroxyphenyl)imidazolidine-2,4-dione, 4-(l-isopropyl- lH-pyrazol-4-yl)phenol, 4-(l,3-dimethyl-lH-pyrazol-4-yl)phenol, 3-methyl-4-(3-methyl-lH- pyrazol-4-yl)phenol, 4-(l,4-dimethyl-lH-pyrazol-5-yl)phenol, 4-(4-hydroxyphenyl)tetrahydro-2H- pyran-4-carbonitrile, 4-(3-amino-5-methyl-lH-pyrazol-4-yl)phenol, 4-(3-(tert-butyl)-5-methyl-methyl-methyl-
  • appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate.
  • the appropriate solvent is THF, DMF or DMA.
  • the reaction temperature is about room temperature to about 90 °C and the reaction time is about 18 hours (overnight).
  • intermediate 1-6 is reacted under Mitsunobu reaction conditions with intermediate 1-9 using appropriate reagents in an appropriate solvent or solvent mixture at an appropriate temperature and an appropriate amount of time to provide intermediate 1-10.
  • the appropriate reagents are triphenylphosphine and diisopropyl azodi carboxyl ate.
  • the appropriate solvent is an ethereal solvent such as THF.
  • the appropriate temperature is about 0 °C to about room temperature. In some embodiments, the appropriate amount of time is about 18 hours (overnight).
  • 1-10 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound I- 11.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM.
  • the reaction is conducted in TFA only.
  • the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • 1-10 is treated with HC1 after reaction with TFA to isolate the hydrochloride salt of compound 1-11.
  • intermediate 1-9 used in the preparation of compounds 1-10 described herein are prepared as outlined in Scheme 2.
  • intermediate 11-13 is prepared from halide 11-12 using boron- halogen exchange conditions.
  • Suitable boron-halogen exchange conditions include but are not limited to use of a suitable organometallic reagent and a suitable boron reagent.
  • suitable organometallic reagents include palladium.
  • suitable boron reagents include bis(pinacolato)diboron.
  • suitable palladium- catalyzed boron-halogen exchange conditions include Pd(dppf)Cl 2 with an appropriate base, in an appropriate solvent for an appropriate time and at an appropriate temperature.
  • intermediate 11-13 is reacted with an aromatic halide (R 3 -halide) under suitable metal-catalyzed cross-coupling reaction conditions to provide intermediate 1-9.
  • the aromatic halide is an aromatic chloride, bromide or iodide.
  • the aromatic halide is 2-chloropyrimidine.
  • suitable metal- catalyzed cross-coupling conditions include use of palladium.
  • suitable palladium-catalyzed cross-coupling reaction conditions include Pd(PPh 3 ) 2 Cl2 with an appropriate base, in an appropriate solvent for an appropriate time and at an appropriate temperature.
  • the base is an inorganic base such as Na 2 C0 3.
  • the appropriate solvent is a dioxane/water, or DMF/water mixture.
  • the appropriate temperature is about 50 °C to about 90 °C.
  • the appropriate time is about 0.5 hours to about 18 hours (overnight).
  • the phenol group of intermediate 11-13 is substituted with an appropriate protecting group prior to the metal -catalyzed cross-coupling reaction and subsequently removed under appropriate conditions.
  • halide 11-12 is reacted with a nitrogen-containing heterocycle under suitable metal-catalyzed cross-coupling reaction conditions to provide A -linked intermediate 1-9.
  • the nitrogen-containing heterocycle is l//-pyrazole.
  • suitable metal-catalyzed cross-coupling conditions include use of copper.
  • suitable copper-catalyzed cross-coupling reaction conditions include the use of copper (I) iodide with an appropriate base in an appropriate solvent for an appropriate time and at an appropriate temperature.
  • an appropriate base is an inorganic base such as cesium carbonate.
  • an appropriate solvent is DMF.
  • the appropriate time and appropriate temperature is about 120 °C for about 18 hours (overnight).
  • the phenol group of intermediate 11-13 is substituted with an appropriate protecting group prior to the metal -catalyzed cross-coupling reaction.
  • the protecting group is a methyl group.
  • deprotection conditions include using boron tribromide with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate solvent is a chlorinated solvent such as DCM.
  • the reaction temperature is about 0 °C to about room temperature and the reaction time is about 18 hours (overnight).
  • aryl halide 11-12 is reacted with a boron reagent under suitable metal -catalyzed cross-coupling reaction conditions to directly provide 1-9.
  • the boron reagent is an aromatic boronic acid.
  • the boron reagent is an aromatic boronic ester.
  • the boron reagent is an aromatic pinacolyl boronic ester.
  • suitable metal-catalyzed cross-coupling conditions include palladium.
  • suitable palladium-catalyzed cross-coupling reaction conditions include Pd(dppf)Cl 2 with an appropriate base, with an appropriate solvent for an appropriate time and at an appropriate temperature.
  • the phenol group of intermediate 11-12 is substituted with an appropriate protecting group prior to metal -catalyzed cross-coupling reaction.
  • compound is prepared from appropriate metal-catalyzed cross coupling conditions of halide 11-12 with a tin reagent.
  • halide 11-12 is a bromide.
  • the tin reagent is an aromatic tin reagent.
  • metal -catalyzed cross couplings include Stille palladium-catalyzed cross-coupling conditions.
  • Suitable palladium catalysts for cross-coupling include but are not limited to Pd(PPh 3 ) 4 in a suitable solvent, such as DMF or dioxane, at a suitable temperature for an appropriate amount of time.
  • a suitable temperature is 90 °C to about 100 °C.
  • the appropriate amount of time is about 2 hours to about 18 hours (overnight).
  • compound 1-9 is directly prepared from appropriate metal- catalyzed cross coupling conditions of halide 11-12 with an aromatic compound.
  • halide 11-12 is a bromide.
  • metal-catalyzed cross couplings include C-H activation cross-coupling conditions.
  • C-H activation cross coupling conditions include use of palladium catalysts.
  • Suitable palladium catalysts for cross coupling include but are not limited to Pd(OAc) 2 with a suitable ligand in a suitable solvent, such as dioxane, with an appropriate base at a suitable temperature for an appropriate amount of time.
  • the suitable ligand is a phosphine ligand.
  • the appropriate base is an inorganic base.
  • the suitable temperature is about 50 °C to about 110 °C.
  • the appropriate amount of time is about 2 hours to about 18 hours (overnight).
  • ketone III-l is treated with a base to form an enolate with an appropriate base, in an appropriate solvent, for an appropriate amount of time, at an appropriate temperature.
  • the base is an organic base.
  • the organic base is LiHMDS.
  • enolate formation takes place at about -78 °C.
  • the appropriate solvent is THF.
  • the appropriate time is about one hour.
  • the enolate of ketone III-l is reacted with a suitable electrophile in an appropriate solvent to form enol ether III-2 at the appropriate temperature, for an appropriate amount of time.
  • the electrophile forms a sulfate ester.
  • the electrophile is PhNTf 2 .
  • the appropriate temperature is about -78 °C and the appropriate time is about 2 hours.
  • the reaction is further warmed to a suitable temperature over a suitable period of time. In some embodiments, the suitable temperature is about room temperature for about overnight.
  • a suitable boronic acid is reacted with enol triflate III-2 under suitable metal -catalyzed cross-coupling reaction conditions to provide III-3.
  • suitable metal-catalyzed cross-coupling conditions include palladium.
  • suitable palladium-catalyzed cross-coupling reaction conditions include Pd(dppf)Cl 2 with an appropriate base, with an appropriate solvent for an appropriate time and at an appropriate temperature.
  • the base is an inorganic base.
  • the inorganic base is a carbonate base such as Na 2 C0 3.
  • the appropriate solvent is a dioxane/water mixture.
  • the appropriate time and appropriate temperature is about 6 hours at about 30 °C. In some embodiments, the appropriate time and appropriate temperature is about 1 to about 18 hours at about 80 °C.
  • III-3 is subjected under suitable olefin reduction conditions to provide III-4.
  • suitable reduction conditions include palladium-catalyzed hydrogenation conditions.
  • palladium-catalyzed hydrogenation conditions include use of 10% Pd/C with hydrogen (1 atm) in a suitable solvent, such as MeOH, for an appropriate amount of time at an appropriate temperature. In some embodiments, the appropriate amount of time is about overnight at about rt.
  • the acylation of amine III-7 affords compound III-4.
  • suitable acylation conditions include the use of acetyl acetate with a suitable base, such as K 2 C0 3 , in a suitable solvent, such as dioxane, for an appropriate amount of time and at a suitable temperature, such as about room temperature for about 2 hours.
  • a suitable base such as K 2 C0 3
  • a suitable solvent such as dioxane
  • the synthetic method further comprises the hydrolysis of the ester intermediate formed in the acylation reaction.
  • suitable ester hydrolysis conditions include the use of a suitable base, such as KOH, in a suitable solvent, such as dioxane/water, for an appropriate amount of time and at a suitable temperature, such as about room temperature for about 4 hours to provide III-4.
  • the reaction of amine III-7 with a sulfonyl chloride affords compound III-4.
  • suitable conditions include the use of MsCl in a suitable solvent, such as dichloromethane, for an appropriate amount of time and at a suitable temperature, such as about room temperature for about 18 hours.
  • X is O
  • the oxygen is also concurrently sulfonated under the reaction conditions.
  • the synthetic method further comprises the hydrolysis of the sulfonate ester intermediate formed in the reaction.
  • suitable sulfonate ester hydrolysis conditions include the use of a suitable base, such as NaOH, in a suitable solvent, such as MeOH/water, for an appropriate amount of time and at a suitable temperature, such as about 80 °C for about 1 hour to provide III-4.
  • a suitable base such as NaOH
  • MeOH/water a suitable solvent
  • suitable temperature such as about 80 °C for about 1 hour to provide III-4.
  • intermediate III-7 is reacted to incorporate a suitable amine protecting group.
  • a suitable protecting group is a Boc group to provide intermediate III-4.
  • suitable conditions include the use of Boc 2 0 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the base is an organic base such as triethylamine.
  • the appropriate solvent is an alcohol solvent such as methanol.
  • the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
  • III-7 is subjected to suitable conditions to incorporate a primary alcohol protecting group.
  • a suitable protecting group is a silyl protecting group such as teoc (2-(trimethylsilyl)ethoxycarbonyl) group, to provide intermediate III-4.
  • conditions include the use of the appropriate silyl-based reagent using an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base is triethylamine.
  • the appropriate solvent is THF.
  • the suitable temperature is about 0 °C to room temperature and the appropriate amount of time is about 18 hours (overnight).
  • III-5 is reacted with intermediate III-4 under suitable conditions to provide intermediate III-6.
  • appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate.
  • the appropriate solvent is THF, DMF or DMA.
  • the reaction temperature is about room temperature to about 90 °C and the reaction time is about 18 hours (overnight).
  • III-6 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound III-8.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM.
  • the reaction is conducted in TFA only.
  • the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • III-6 is treated with HC1 after reaction with TFA to isolate the hydrochloride salt of compound III-8.
  • compounds described herein are prepared as outlined in Scheme 4.
  • intermediate III-6 wherein R la is a Boc protecting group
  • intermediate III-6 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound IV- 1.
  • the appropriate solvent is THF.
  • the reaction temperature is about room temperature and the reaction time is about 18 hours (overnight).
  • intermediate III-6 wherein R la is a teoc (2- (trimethylsilyl)ethoxycarbonyl) group protecting group
  • intermediate III-6 is reacted with tetra-n- butylammonium fluoride in an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound IV-1.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM.
  • the reaction is conducted in TFA only.
  • the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • acylation of amine IV-1 with an acyl chloride affords compound IV-2.
  • Suitable acylation conditions include but are not limited to the use of a suitable base, such as TEA or pyridine in a suitable solvent, such as DCM or toluene, for an appropriate amount of time and at a suitable temperature, such as about room temperature to about 80 °C for about 1 hour to about overnight.
  • a suitable base such as TEA or pyridine
  • a suitable solvent such as DCM or toluene
  • pyridine is used as both the base and the solvent.
  • conditions include the addition of DMAP.
  • reaction of amine IV-1 with a sulfonyl chloride affords compound IV-3.
  • suitable conditions include the use of an alkylsufonyl chloride in a suitable solvent, such as dichloromethane, for an appropriate amount of time and at a suitable temperature, such as about room temperature for about 18 hours.
  • the alkylation of amine IV-1 with an alkyl halide affords compound IV-4.
  • an appropriate alkyl halide is an alkyl chloride.
  • suitable alkylation conditions include but are not limited to the use of a suitable base, such as TEA or pyridine in a suitable solvent, such as DMF, for an appropriate amount of time and at a suitable temperature, such as about room temperature to about 80 °C for about 1 hour to about overnight.
  • IV-2 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound IV-5.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • IV-3 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound IV-6.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight). [00242] In some embodiments, IV-4 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound IV-7. In some embodiments, the appropriate acid is HC1 or TFA. In some
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • X is -0-. In some embodiments, Z is F. In some embodiments, n is 0. In some embodiments, p is 1.
  • intermediate V-l is reacted with methyl carbonochloridate with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound V-2.
  • the appropriate solvent is Et 2 0, dioxane, MeCN, or THF.
  • the reaction temperature is about room temperature and the reaction time is about 2 hours.
  • V-3 is reacted with intermediate V-2 under suitable conditions to provide intermediate V-4.
  • appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate.
  • the appropriate solvent is THF, DMF or DMA.
  • the reaction temperature is about 50 °C to about 60 °C and the reaction time is about 18 hours (overnight).
  • V-4 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound V-5.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM.
  • the reaction is conducted in TFA only.
  • the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • X is -0-. In some embodiments, Z is F. In some embodiments, n is 0. In some embodiments, p is 1.
  • intermediate VI-1 is reacted with a cabamoyl chloride with an appropriate base and an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound VI-2.
  • the cabamoyl chloride is methylcarbamic chloride.
  • the appropriate base is triethylamine or pyridine.
  • the appropriate solvent is DCM or DMF.
  • the reaction temperature is about room temperature and the reaction time is about 18 hours.
  • VI-2 is reacted with VI-3 under suitable conditions to provide intermediate VI-4.
  • appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate.
  • the appropriate solvent is THF, DMF or DMA.
  • the reaction temperature is about 50 °C to about 60 °C and the reaction time is about 18 hours (overnight).
  • VI-2 is reacted with VI-3 under suitable conditions to provide intermediate VI-5.
  • appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate.
  • the appropriate solvent is THF, DMF or DMA.
  • the reaction temperature is about 50 °C to about 60 °C and the reaction time is about 18 hours (overnight).
  • intermediate VI-5 is reacted with a cabamoyl chloride with an appropriate base and an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound VI-4.
  • the cabamoyl chloride is methylcarbamic chloride.
  • the appropriate base is triethylamine or pyridine.
  • the appropriate solvent is DCM.
  • the reaction temperature is about room temperature and the reaction time is about 18 hours.
  • VI-4 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound VI-6.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • X is -0-. In some embodiments, Z is F. In some embodiments, n is 0. In some embodiments, p is 1.
  • VII-1 is reacted with VII-2 under suitable conditions to provide intermediate VII-3.
  • appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate.
  • the appropriate solvent is THF, DMF or DMA.
  • the reaction temperature is about 50 °C to about 60 °C and the reaction time is about 18 hours (overnight).
  • VII-3 is subjected to suitable nitro functional group reduction conditions to provide aniline VII-4.
  • suitable nitro reduction conditions include use of iron powder and ammonium chloride in a suitable solvent or solvent mixture, such as ethanol/water, for an appropriate amount of time at an appropriate temperature.
  • the reaction temperature is about 90 °C and the reaction time is about 2 hours.
  • the reaction of aniline VII-4 with a sulfonyl chloride affords compound VII-5.
  • suitable conditions include the use of an alkylsufonyl chloride with a suitable base, such as triethylamine, in a suitable solvent, such as dichloromethane, for an appropriate amount of time and at a suitable temperature, such as about room temperature for about 18 hours.
  • VII-5 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound VII-6.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • a suitable boronic ester VIII-1 is reacted with aryl bromide or idodie VIII-2 under suitable metal-catalyzed cross-coupling reaction conditions to provide VIII-3.
  • suitable metal-catalyzed cross-coupling conditions include palladium.
  • suitable palladium-catalyzed cross-coupling reaction conditions include Pd(dppf) 2 Cl 2 with an appropriate base, with an appropriate solvent for an appropriate time and at an appropriate temperature.
  • the base is an inorganic base.
  • the inorganic base is a carbonate base such as K 2 C0 3.
  • the appropriate solvent is a dioxane/water mixture.
  • the appropriate time and appropriate temperature is about 1 hour at about 100 °C.
  • VIII-3 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound VIII-4.
  • the appropriate acid is TFA.
  • the appropriate solvent is DCM.
  • the reaction temperature is about room temperature and the reaction time is about 1 hour.
  • acylation of amine VIII-4 affords compound VIII-5.
  • suitable acylation conditions include the use of acetic anhydride with a suitable base, such as Et 3 N, in a suitable solvent, such as DCM, for an appropriate amount of time and at a suitable temperature, such as about room temperature for about 1 hour.
  • VIII-5 is subjected under suitable olefin reduction conditions to provide VIII-6.
  • suitable reduction conditions include palladium-catalyzed hydrogenation conditions.
  • suitable palladium-catalyzed hydrogenation conditions also concurrently removes the phenol protecting group.
  • the phenol protecting group is a benzyl group.
  • hydrogenation conditions include use of 10% Pd/C with hydrogen (1 atm) in a suitable solvent, such as MeOH, for an appropriate amount of time at an appropriate temperature.
  • a suitable solvent such as MeOH
  • the appropriate amount of time is about overnight at about room temperature.
  • VIII-6 is reacted with intermediate VIII-7 under suitable conditions to provide intermediate VIII-8.
  • appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate.
  • the appropriate solvent is THF, DMF or DMA.
  • the reaction temperature is about room temperature to about 90 °C and the reaction time is about 18 hours (overnight).
  • VIII-8 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound VIII-9.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM.
  • the reaction is conducted in TFA only.
  • the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • VIII-8 is treated with HC1 after reaction with TFA to isolate the hydrochloride salt of compound VIII-9.
  • IX-1 is reacted with intermediate IX-2 under suitable alkylation conditions to provide intermediate IX-3.
  • appropriate alkylation conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base is sodium hydride.
  • the appropriate solvent is DMF.
  • the reaction temperature is about 0 °C to about room temperature and the reaction time is about 1 hour to about 18 hours (overnight).
  • IX-3 is subjected to suitable benzyl deprotection conditions to provide IX-4.
  • suitable deprotection conditions include palladium-catalyzed hydrogenation conditions.
  • appropriate conditions include using an appropriate palladium catalyst under a suitable pressure of hydrogen with an appropriate solvent or solvent mixture for an appropriate amount of time and at an appropriate temperature.
  • the appropriate palladium catalyst is palladium on carbon.
  • a suitable pressure of hydrogen is about atmospheric pressure to about 50 PSI.
  • the appropriate solvent is methanol.
  • the reaction temperature is about room temperature and the reaction time is about 1 hour to 18 hours (overnight).
  • IX-4 is reacted with intermediate IX-5 under suitable conditions to provide intermediate IX-6.
  • appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate.
  • the appropriate solvent is THF, DMF or DMA.
  • the reaction temperature is about room temperature to about 90 °C and the reaction time is about 18 hours (overnight).
  • IX-6 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound IX-7.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM.
  • the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • IX-6 is treated with HC1 after reaction with TFA to isolate the hydrochloride salt of compound IX-7.
  • compounds are prepared as described in the Examples.
  • Ci-C x includes Ci-C 2 , C 1 -C 3 . . . Ci-C x.
  • a group designated as "C 1 -C 4 " indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
  • C 1 -C 4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, /50-propyl, «-butyl, /.so -butyl, .sfc-butyl, and /-butyl.
  • An“alkyl” group refers to an aliphatic hydrocarbon group.
  • the alkyl group is branched or straight chain.
  • the“alkyl” group has 1 to 10 carbon atoms, i.e. a Ci- Cioalkyl.
  • a numerical range such as“1 to 10” refers to each integer in the given range; e.g.,“1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • an alkyl is a Ci-C 6 alkyl.
  • the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
  • An“alkylene” group refers refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl.
  • an alkylene is a Ci-C 6 alkylene.
  • an alkylene is a Ci-C 4 alkylene.
  • an alkylene comprises one to four carbon atoms (e.g., Ci- C 4 alkylene).
  • an alkylene comprises one to three carbon atoms (e.g., C 1 -C 3 alkylene).
  • an alkylene comprises one to two carbon atoms (e.g., Ci-C 2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises two carbon atoms (e.g., C 2 alkylene). In other embodiments, an alkylene comprises two to four carbon atoms (e.g., C 2 -C alkylene).
  • Typical alkylene groups include, but are not limited to, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, - CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and the like.
  • Deuteroalkyl refers to an alkyl group where 1 or more hydrogen atoms of an alkyl are replaced with deuterium.
  • alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present.
  • R is H or an alkyl.
  • an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like.
  • alkynyl refers to a type of alkyl group in which at least one carbon-carbon triple bond is present.
  • an alkenyl group has the formula -CoC-R, wherein R refers to the remaining portions of the alkynyl group.
  • R is H or an alkyl.
  • an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Non-limiting examples of an alkynyl group include -CoCH, -CoCCH 3 -CoCCH 2 CH 3 , - CH 2 CoCH.
  • An“alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.
  • alkylamine refers to the -N(alkyl) x H y group, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.
  • the term“aromatic” refers to a planar ring having a delocalized p-electron system containing 4n+2 p electrons, where n is an integer.
  • the term“aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or“heteroaryl” or“heteroaromatic”) groups (e.g., pyridine).
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon or nitrogen atoms) groups.
  • the term“carbocyclic” or“carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from“heterocyclic” rings or“heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycle includes cycloalkyl and aryl.
  • aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some
  • an aryl is a phenyl. In some embodiments, an aryl is a C 6 -C l0 aryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).
  • cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • cycloalkyls are spirocyclic or bridged compounds.
  • cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom.
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbomyl and bicyclo[l. l. l]pentyl.
  • a cycloalkyl is a C 3 - C 6 cycloalkyl.
  • a cycloalkyl is a monocyclic cycloalkyl.
  • Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2. l]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2. l]heptanyl, and the like
  • halo or, alternatively,“halogen” or“halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
  • haloalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a halogen atom.
  • a fluoroalkyl is a Ci-C 6 fluoroalkyl.
  • fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
  • a fluoroalkyl is a Ci-C 6 fluoroalkyl.
  • a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
  • heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g ., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-, sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a Ci-C 6 heteroalkyl.
  • heteroalkylene refers refers to a divalent heteroalkyl radical.
  • heterocycle refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms.
  • heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic or bridged compounds.
  • Non-aromatic heterocyclic groups include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system.
  • the heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl,
  • l]octanyl 3H-indolyl, indolin-2-onyl, isoindolin-l-onyl, isoindoline-l,3-dionyl, 3,4- dihydroisoquinolin-l(2H)-onyl, 3,4-dihydroquinolin-2(lH)-onyl, isoindoline-l,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, lH-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl.
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a group derived from pyrrole includes both pyrrol-l-yl (A-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both A-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached).
  • the heterocyclic groups include benzo-fused ring systems.
  • at least one of the two rings of a bicyclic heterocycle is aromatic.
  • both rings of a bicyclic heterocycle are aromatic.
  • heteroaryl or, alternatively,“heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls.
  • Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
  • Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, l,8-naphthyridine, and pteridine.
  • a heteroaryl contains 0-4 N atoms in the ring.
  • a heteroaryl contains 1-4 N atoms in the ring.
  • a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring.
  • a heteroaryl contains 1-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring.
  • heteroaryl is a Ci-Cgheteroaryl.
  • monocyclic heteroaryl is a Ci-Csheteroaryl.
  • monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl.
  • bicyclic heteroaryl is a C 6 -C 9 heteroaryl.
  • A“heterocycloalkyl” or“heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur.
  • a heterocycloalkyl is fused with an aryl or heteroaryl.
  • the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,
  • heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
  • a heterocycloalkyl is a C2-Cioheterocycloalkyl.
  • a heterocycloalkyl is a C4-Cioheterocycloalkyl.
  • a heterocycloalkyl contains 0- 2 N atoms in the ring.
  • a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.
  • bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • bond when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
  • moiety refers to a specific segment or functional group of a molecule.
  • Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • optional substituents are independently selected from D, halogen, -CN, -NH 2 , -OH, -NH(CH 3 ), -N(CH 3 ) 2 , - CH 3 , -CH 2 CH 3 , -CF 3 , -OCH 3 , and -OCF 3 .
  • substituted groups are substituted with one or two of the preceding groups.
  • module means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • modulator refers to a molecule that interacts with a target either directly or indirectly.
  • the interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof.
  • a modulator is an agonist.
  • administered refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.
  • co-administration or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • an“effective amount” or“therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an“effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate“effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

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Abstract

L'invention concerne des composés qui sont des inhibiteurs d'amine oxydase sensible au semicarbazide (SSAO), des procédés de fabrication de tels composés, des compositions pharmaceutiques et des médicaments comprenant de tels composés, et des procédés d'utilisation de tels composés dans le traitement ou la prévention d'une maladie ou d'une pathologie hépatique.
PCT/US2019/037380 2018-06-15 2019-06-14 Inhibiteurs de ssao et leurs utilisations Ceased WO2019241751A1 (fr)

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US11820754B2 (en) 2020-08-25 2023-11-21 Eli Lilly And Company Polymorphs of an SSAO inhibitor
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Publication number Priority date Publication date Assignee Title
WO2020125776A1 (fr) * 2018-12-20 2020-06-25 山东丹红制药有限公司 Voie de traitement d'un composé de formule (iv), forme cristalline et procédé de préparation associée
US12077513B2 (en) 2018-12-20 2024-09-03 Shandong Danhong Pharmaceutical Co., Ltd. Process route of compound of formula (IV), crystal form and preparation method therefor
WO2021083209A1 (fr) * 2019-10-29 2021-05-06 Eccogene (Shanghai) Co., Ltd. Inhibiteurs de ssao et leur utilisation
US11472769B2 (en) 2019-10-29 2022-10-18 Eccogene (Shanghai) Co., Ltd. SSAO inhibitors and use thereof
EP4051669A4 (fr) * 2019-10-29 2023-12-13 Eccogene (Shanghai) Co., Ltd. Inhibiteurs de ssao et leur utilisation
US11964942B2 (en) 2019-10-29 2024-04-23 Eccogene (Shanghai) Co., Ltd. SSAO inhibitors and use thereof
WO2021148032A1 (fr) * 2020-01-23 2021-07-29 轶诺(浙江)药业有限公司 Préparation d'un inhibiteur de l'amine oxydase sensible au semicarbazide et son utilisation
US12486244B2 (en) 2020-01-23 2025-12-02 Ennovabio (Zhejiang) Pharmaceuticals Co., Ltd. Preparation of semicarbazide-sensitive amine oxidase inhibitor and use thereof
US11820754B2 (en) 2020-08-25 2023-11-21 Eli Lilly And Company Polymorphs of an SSAO inhibitor
WO2024172156A1 (fr) * 2023-02-16 2024-08-22 国立大学法人東海国立大学機構 Composé ayant une activité de type brassinostéroïde
WO2025107036A1 (fr) * 2023-11-23 2025-05-30 Syntara Limited Inhibiteurs doubles d'amines oxydases et de peroxydases et leurs utilisations

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